5,6,7-trihydroxyheptanoic acid and analogs for the treatment of ocular diseases and diseases associated with hyperproliferative and angiogenic responses

ABSTRACT

Compositions containing 5,6,7-trihydroxyheptanoic acid and analogs and their use for treating posterior segment ocular diseases and diseases characterized by cellular hyperproliferation or angiogenesis, are disclosed.

The present application is a divisional of U.S. patent application Ser.No. 11/268,968 filed Nov. 8, 2005, which claims priority to provisionalapplication, U.S. Patent Application Ser. No. 60/626,209 filed Nov. 9,2004.

The present invention is directed to 5,6,7-trihydroxyheptanoic acid andanalogs and their methods of use, including in ophthalmic compositions.The compounds are particularly useful in treating persons suffering fromposterior segment ocular diseases such as diabetic retinopathy andage-related macular degeneration, and disorders characterized bycellular hyperproliferation and angiogenesis, such and as rheumatoidarthritis, coronary artery restenosis after balloon angioplasty, andcancer.

BACKGROUND OF THE INVENTION

Conditions characterized by cellular hyperproliferation, such as chronicinflammation, ischemic diseases, and cancer are often accompanied byintense angiogenesis, a highly orchestrated process involving vesselsprouting, endothelial cell migration, proliferation, and maturation.Endothelial cells are normally quiescent but become activated during theangiogenic response. Upon stimulation, endothelial cells can degradetheir basement membrane and proximal extracellular matrix, migratedirectionally, then divide and organize into functional capillariesinvested by a new basal lamina.

Posterior segment neovascularization (NV) is the vision-threateningpathology responsible for the two most common causes of acquiredblindness in developed countries: exudative age-related maculardegeneration (wet AMD) and proliferative diabetic retinopathy (PDR).Currently there are several approved treatments in the United States fortreating the posterior segment NV that occurs during wet AMD. Laserphotocoagulation involves thermal destruction of the neovascular lesionwith a laser, which because of the vagaries of laser targeting andthermal energy transfer leads to collateral destruction of somesurrounding tissue. Photodynamic therapy with Visudyne® solutioninvolves intravenous administration of the solution to the patient,after which time a red laser is shone into the AMD-affected eye(s). Theresultant photon absorption by the porphyrin active ingredient producesan electronically excited state that transfers energy to oxygen toproduce reactive oxygen species. Use of strictly pharmacologicaltherapies commenced in late 2004 with the approval in the United Statesof the VEGF-binding aptamer pegaptanib sodium (Macugen® solution) forthe treatment of wet AMD. Surgical interventions with vitrectomy andmembrane removal are the only options currently available for patientswith proliferative diabetic retinopathy. Other pharmacologic treatmentbeing evaluated clinically for the treatment of wet AMD and for diabeticretinopathy include anecortave acetate (Alcon, Inc.) and rhuFabV2(Genentech) for AMD and LY333531 (Lilly) and Fluocinolone (Bausch &Lomb) for diabetic macular edema.

Non-exudative (dry) AMD can progress to wet AMD as described below. In anormally functioning retina, photoreceptors are supported by specializedcells in the retinal pigmented epithelium (RPE). These RPE cells take upreleased 11-trans retinaldehyde (in the form of the reduced retinol) andisomerize the olefin geometry back to the photoactive 11-cis form. RPEcells also phagocytose photoreceptor outer membrane segments that arecontinuously shed and replaced. Choroidal capillaries providenutritional support (oxygen, proteins, hormones, etc.) to and removewaste products from photoreceptors and RPE cells, and are separated fromthem by Bruch's membrane. It is believed that a normally functioningBruch's membrane is sufficiently permeable to allow diffusional exchangeof nutrition and waste products between the choroidal capillaries andRPE cells. In dry AMD there is increased deposition of insolublematerial within Bruch's membrane, leading to protein cross-linking. Theaccumulation of hydrophobic material may be a consequence of inefficientphagocytosis, and may precipitate an inflammatory response. Over timethe membrane thickens and consequently has decreased permeability bothto oxygen (and plasma-borne nutrients) from the choroidal capillariesand to waste products from RPE cells. RPE cells may die from theresulting metabolic distress. Without their RPE support cells, theassociated photoreceptors in the macula die. This loss of macularphotoreceptors is termed geographic atrophy. As the photoreceptors die,central visual acuity is gradually lost. Additionally, RPE cells mayrespond to the hypoxic condition resulting from Bruch's membranethickening by secreting pro-angiogenic proteins in an attempt tore-establish adequate blood flow. The most important of these proteinsis vascular endothelial growth factor (VEGF). VEGF promotes theproliferation of new capillaries from existing ones, and these breachBruch's membrane. This leads to macular accumulation of fluid and bloodfrom the leaky new vessels (VEGF is a potent blood vesselpermeability-increasing factor) and formation of fibrous deposits andscar tissue in the retina, rapidly causing retinal detachment andtherefore loss of visual function. Thus treating dry AMD by rescuing RPEcells from metabolic distress-induced cell death should also inhibitdisease progression to wet AMD.

With respect to diabetic retinopathy, in addition to changes in theretinal microvasculature induced by hyperglycemia in diabetic patientsleading to macular edema, proliferation of neovascular membranes is alsoassociated with vascular leakage and edema of the retina. Where edemainvolves the macula, visual acuity decreases. In diabetic retinopathy,macular edema is the major cause of vision loss. Like angiogenicdisorders, laser photocoagulation is used to stabilize or resolve theedematous condition. While reducing further development of edema, laserphotocoagulation is a cytodestructive procedure, that, unfortunatelywill decrease vision in the affected eye.

A pharmacologic therapy for ocular NV and edema would providesubstantial efficacy to the patient, in many diseases thereby avoidinginvasive surgical or damaging laser procedures. Effective treatment ofthe NV and edema would improve the patient's quality of life andproductivity within society. Also, societal costs associated withproviding assistance and health care to the blind could be dramaticallyreduced.

Excessive angiogenesis of the blood vessels in the synovial lining ofthe joints is thought to play an important role in rheumatoid arthritis.In addition to forming new vascular networks, the endothelial cellsrelease factors and reactive oxygen species that lead to pannus growthand cartilage destruction. It is believed that the factors involved inangiogenesis can actively contribute to, and help maintain, thechronically inflamed state of rheumatoid arthritis. It is believed thatfactors associated with angiogenesis can also have a role inosteoarthritis. The activation of the chondrocytes by angiogenic-relatedfactors contributes to the destruction of the joint. At a later stage,the angiogenic factors can promote new bone formation.

Often times, cancer is associated with angiogenesis and is identified bysolid tumor formation and metastasis. A tumor cannot expand without ablood supply to provide nutrients and remove cellular wastes. Tumors inwhich angiogenesis is important include solid tumors, and benign tumorssuch as acoustic neuroma, neurofibroma, trachoma and granulomas.Prevention or inhibition of angiogenesis could prevent or halt thegrowth of these tumors and the subsequent degenerative condition due tothe presence of the tumor.

Angiogenesis has also been associated with blood-born tumors includingleukemias, any of the various acute or chronic neoplastic diseases ofbone marrow in which unrestrained proliferation of white blood cellsoccurs, usually accompanied by anemia, impaired blood clotting, andenlargement of the lymph nodes, liver, and spleen. It is believed thatangiogenesis is significant as a caustive factor in the abnormalities inthe bone marrow that give rise to leukemia-like tumors.

Angiogenesis is important in two stages of tumor metastasis. The firststage where angiogenesis stimulation is important is in thevascularization of the tumor which allows tumor cells to enter the bloodstream and to circulate throughout the body. Once the tumor cells leavethe primary site, and find a secondary metastasis site, angiogenesismust occur before the new tumor can grow and expand. Therefore,prevention of angiogenesis could prevent metastasis of tumors andcontain the cancerous growth to the primary site.

Many individuals suffer from heart disease caused by a partial blockageof the blood vessels that supply the heart with nutrients. More severeblockage of blood vessels in such individuals often leads tohypertension, ischemic injury, stroke, or myocardial infarction.Typically vascular occlusion is preceded by vascular stenosis resultingfrom intimal smooth muscle cell hyperplasia. The underlying cause of theintimal smooth muscle cell hyperplasia is vascular smooth muscle injuryand disruption of the integrity of the endothelial lining. Restenosis isa process of smooth muscle cell migration and proliferation at the siteof percutaneous transluminal coronary balloon angioplasty, which hampersthe success of angioplasty. For both vascular stenosis and restenosissecondary to balloon angioplasty, the overall disease process can betermed a hyperproliferative vascular disease because of the etiology ofthe disease process.

There are many agents known to inhibit angiogenesis. For example,steroids functioning to inhibit angiogenesis in the presence of heparinor specific heparin fragments are disclosed in Crum, et al., A New Classof Steroids Inhibits Angiogenesis in the Presence of Heparin or aHeparin Fragment, Science, Vol. 230:1375-1378, Dec. 20, 1985. Theauthors refer to such steroids as “angiostatic” steroids. Includedwithin this class of steroids found to be angiostatic are the dihydroand tetrahydro metabolites of cortisol and cortexolone. In a follow-upstudy directed to testing a hypothesis as to the mechanism by which thesteroids inhibit angiogenesis, it was shown that heparin/angiostaticsteroid compositions cause dissolution of the basement membranescaffolding to which anchorage dependent endothelia are attachedresulting in capillary involution; see, Ingber, et al., A PossibleMechanism for Inhibition of Angiogenesis by Angiostatic Steroids:Induction of Capillary Basement Membrane Dissolution, Endocrinology Vol.119:1768-1775, 1986.

A group of tetrahydro steroids useful in inhibiting angiogenesis isdisclosed in U.S. Pat. No. 4,975,537, Aristoff, et al. The compounds aredisclosed for use in treating head trauma, spinal trauma, septic ortraumatic shock, stroke, and hemorrhage shock. In addition, the patentdiscusses the utility of these compounds in embryo implantation and inthe treatment of cancer, arthritis, and arteriosclerosis. Some of thesteroids disclosed in Aristoff et al. are disclosed in U.S. Pat. No.4,771,042 in combination with heparin or a heparin fragment forinhibiting angiogenesis in a warm blooded animal.

Compositions of hydrocortisone, “tetrahydrocortisol-S,” and U-72,745G,each in combination with a beta cyclodextrin, have been shown to inhibitcorneal neovascularization: Li, et al., Angiostatic Steroids Potentiatedby Sulphated Cyclodextrin Inhibit Corneal Neovascularization,Investigative Ophthalmology and Visual Science, Vol. 32(11):2898-2905,October, 1991. The steroids alone reduce neovascularization somewhat butare not effective alone in effecting regression of neovascularization.

Tetrahydrocortisol (THF) has been disclosed as an angiostatic steroid inFolkman, et al., Angiostatic Steroids, Ann. Surg., Vol. 206(3),374-383,1987, wherein it is suggested angiostatic steroids may havepotential use for diseases dominated by abnormal neovascularization,including diabetic retinopathy, neovascular glaucoma, and retrolentalfibroplasia.

It has been previously shown that certain nonsteroidal anti-inflammatorydrugs (NSAIDs) can inhibit angiogenesis and vascular edema in pathologicconditions. The ability of most NSAIDs to influence vascularpermeability, leading to edema, and angiogenesis appears to beassociated with their ability to block the cyclo-oxygenase enzymes(COX-1 and -2). Blockade of COX-1 and -2 is associated with a decreasein inflammatory mediators, such as PGE₂. Moreover, it appears that PGE₂inhibition results in decreased expression and production of variouscytokines including vascular endothelial growth factor (VEGF). VEGF isknown to produce vascular leakage and angiogenesis in the eye ofpreclinical models. Also, increased levels of VEGF have been found inneovascular tissues and extracellular fluid from the eyes of patientswith diabetic retinopathy and age-related macular degeneration. Thus,NSAIDs may inhibit vascular leakage and angiogenesis by modulating PGE₂levels and its effects on VEGF expression and activity. This theory issupported by work involving animal tumor models which demonstrate thatsystemic administration of COX-2 inhibitors decreases PGE₂ and VEGFtissue levels and thereby prevents tumor-induced angiogenesis. In thesemodels, VEGF activity and angiogenesis are restored by adding exogenousPGE₂ during continued COX-2 blockade. However, NSAIDs appear to havevariable activity in animal models of ocular neovascularization (NV), inthat selective COX inhibitors do not appear to inhibit choroidalneovascularization. In fact, these studies have called into question therole of COX-1 and/or COX-2 in the development of CNV.

As described in commonly owned U.S. application Ser. No. 09/929,381, itwas found that certain 3-benzoylphenylacetic acids and derivatives,which are NSAIDs, are useful for treating angiogenesis-relateddisorders.

Lee et. al. have disclosed that compounds 1 and 2 inhibit LTB₄-inducedchemotaxis of neutrophils as potently as lipoxin A₄ [Lee et. al.,Biochemical and Biophysical Research Communications 1991, 180(3),1416-21]. It is unclear if 1 and 2 act via activation of the lipoxin A₄receptor (ALXR), as the authors did not attempt to reverse theirchemotaxis inhibition using an ALXR antibody or small moleculefunctional antagonist. No other biological data for compounds 1 or 2 hasappeared in the art.

Lipoxin A₄ and certain analogs thereof have been reported to beanti-inflammatory agents (see for example Serhan et. al., U.S. Pat. No.5,441,951). It has been reported that aspirin treatment of activatedleukocytes induces the biosynthesis of 15-epi-lipoxin A₄(aspirin-triggered lipoxin or ATL) from arachidonic acid, by convertingthe cyclooxygenase activity of the COX-2 isozyme into lipoxygenaseactivity [Serhan, Charles N. et. al., J. Pharmacol. Exp. Ther. 1998,287, 779; Serhan, Charles N. et. al. Clin. Chem. Lab. Med. 1999, 37,299].

Aspirin has also been associated with anti-cancer [Current Topics inPharmacology 2002, 6, 25-39; Nature Medicine (New York) 1999, 5(12),1348-1349] and anti-angiogenesis effects, which may occur partly throughthe intermediacy of ATL [Anticancer Research 2001, 21(6A), 3829-3837; JP08268886 A2 (CAN 126:65396); the use of aspirin in combination with thediphenylcyanopentenoic acid, satigrel, for treating diabetic retinopathyis also disclosed in this application]. Lipoxin analog 3 has been shownto inhibit both VEGF- and leukotriene D₄-induced endothelial cellchemotaxis and proliferation in vitro, and to inhibit VEGF-inducedangiogenesis in a murine chronic granulomatous air pouch model in vivo[Fierro et al., J. Pharm. Expt. Ther. 2002, 300(2), 385-392].

The use of lipoxin A₄ and certain analogs, including 3, for treatingangiogenesis-dependent diseases, including ocular neovascular diseasessuch as age-related macular degeneration and diabetic retinopathy, hasbeen disclosed (Serhan and Fierro, U.S. Pat. No. 6,627,658 B1). Howeverto the best of our knowledge no compounds of formula I have been claimedfor posterior segment ocular disorders such as AMD and diabeticretinopathy or cellular hyperproliferative and angiogenesis-dependentdiseases such as cancer, rheumatoid arthritis, and coronary arteryrestenosis after balloon angioplasty.

SUMMARY OF THE INVENTION

The present invention is directed to the use of5,6,7-trihydroxyheptanoic acid and analogs to treat persons sufferingfrom ocular posterior segment ocular disorders, such as dry AMD; ocularposterior segment neovascular and edematous disorders such as diabeticretinopathy and wet AMD; and diseases characterized by cellularhyperproliferation or excessive angiogenesis, such as rheumatoidarthritis, cancer, and vascular restenosis secondary to a percutaneoustransluminal coronary angioplasty procedure.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the claimed invention are useful for the treatment ofdry AMD and as inhibitors of cellular hyperproliferation, such as occursduring pathological angiogenesis. One aspect of the present inventionpertains to methods for the prevention, reduction, or inhibition ofangiogenesis. The method is accomplished by the administration of aneffective amount of one or more compounds of the5,6,7-trihydroxyhepatanoic acid class, and pharmaceutically acceptablesalts, esters, amides or prodrugs thereof, to a subject in need thereof.As a consequence of the action of the therapeutic agent, dry AMD orangiogenesis is prevented or inhibited in the subject.

Another aspect of the present invention pertains to treatment of a dryAMD-affected patient with one or more 5,6,7-trihydroxyheptanoic acidanalogs of the present invention. These compounds are also useful forslowing the progression of dry AMD to wet AMD.

Another aspect of the present invention pertains to treatment of anocular neovascular or edematous disorder, by treatment of the affectedpatient with one or more 5,6,7-trihydroxyheptanoic acid analogs of thepresent invention. The compounds of the present invention areparticularly useful for treating wet AMD and diabetic retinopathy andtheir associated sequellae, such as diabetic macular edema. Other ocularneovascularization-dependent diseases that may be treated in a humanpatient with one or more 5,6,7-trihydroxyheptanoic acid analogs of thepresent invention include chronic glaucoma, retinal detachment, sicklecell retinopathy, age-related macular degeneration, rubeosis iritis,uveitis, neoplasms, Fuch's heterochromic iridocyclitis, neovascularglaucoma, corneal neovascularization, neovascularization resulting fromcombined vitrectomy and lensectomy, retinal ischemia, choroidal vascularinsufficiency, choroidal thrombosis, carotid artery ischemia, contusiveocular injury, retinopathy of prematurity, retinal vein occlusion,proliferative vitreoretinopathy, corneal angiogenesis, and retinalmicrovasculopathy

Another aspect of the present invention pertains to treatment andprevention of rheumatoid and osteoarthritis, by treatment of theaffected patient with one of more 5,6,7-trihydroxyheptanoic acid analogsof the present invention.

Another aspect of the present invention pertains to methods for theprevention or inhibition of solid tumor tissue growth undergoingneovascularization in a subject. The method is accomplished by theadministration of an effective amount of one or more compounds of the5,6,7-trihydroxyhepatanoic acid class, and pharmaceutically acceptablesalts, esters, amides or prodrugs thereof, to a subject in need thereof.

Another aspect of the present invention pertains to inhibition,reduction, or prevention of vascular stenosis or restenosis secondary toa percutaneous transluminal coronary angioplasty procedure, by treatmentof the affected patient with one of more 5,6,7-trihydroxyheptanoic acidanalogs of the present invention. For prevention of restenosis thesecompounds can be administered preferably either orally, via intravenousinjection, or using a drug-impregnated stent. For oral or intravenousdelivery, treatment of the affected patient can commence several daysbefore the operation or after the angioplasty procedure for from about 2to about 28 days, and more typically for about the first 14 daysfollowing the procedure.

5,6,7-Trihydroxyheptanoic acid analogs useful for the methods of thepresent invention are those of formula I:

wherein:R¹ is C₂H₅, CO₂R, CONR²R³, CH₂OR⁴, or CH₂NR⁵R⁶;R is H, C₁-C₆ straight chain or branched alkyl, C₃-C₆ straight chain orbranched alkenyl, C₃-C₆ straight chain or branched alkynyl, C₃-C₆cycloalkyl, or phenyl; or R¹ is a carboxylate salt of formula CO₂ ⁻R⁺,where R⁺ is Li⁺, Na⁺, K⁺, or an ammonium moiety of formula ⁺NR¹⁰R¹²R¹³,where R¹⁰, R¹¹, R¹², and R¹³ are independently H or C₁-C₆ straight chainor branched alkyl, each alkyl group optionally bearing an OH or OCH₃substituent;R², R³ are independently H, C₁-C₆ straight chain or branched alkyl,C₃-C₆ straight chain or branched alkenyl, C₃-C₆ straight chain orbranched alkynyl, C₃-C₆ cycloalkyl, benzyl, phenyl, OH, OCH₃, or OC₂H₅,provided that at most only one of R², R³ is OH, OCH₃, or OC₂H₅;R⁴ is H, C(O)R¹⁴, C₁-C₆ straight chain or branched alkyl, C₃-C₆ straightchain or branched alkenyl, C₃-C₆ straight chain or branched alkynyl,C₃-C₆ cycloalkyl benzyl, or phenyl;R⁵, R⁶ are independently H, C(O)R¹⁴ C₁-C₆ straight chain or branchedalkyl, C₃-C₆ straight chain or branched alkenyl, C₃-C₆ straight chain orbranched alkynyl, C₃-C₆ cycloalkyl, benzyl, phenyl, OH, OCH₃, or OC₂H₅,provided that at most only one of R⁵, R⁶ is OH, OCH₃, or OC₂H₅;

X is O, CH₂, or S;

R⁷, R⁸, and R⁹ are independently H, CH₃, C₂H₅, C(O)R¹⁴, C(O)NR¹⁴R¹⁵, orCO₂R¹⁵;or R⁷ and R⁸ or R⁸ and R⁹ together constitute a carbonyl group (C═O),thus forming a cyclic carbonate;or OR⁸R¹ together form a cyclic ester (a lactone);R¹⁴ and R¹⁵ are H, C₁-C₆ straight chain or branched alkyl, C₃-C₆straight chain or branched alkenyl, C₃-C₆ straight chain or branchedalkynyl, C₃-C₆ cycloalkyl, benzyl, or phenyl; and

indicates that the OR⁹ substituent can be arranged to afford the R or Sabsolute configuration at that position:

Preferred for methods of use of this invention are those compounds offormula I wherein:

R¹ is C₂H₅, CO₂R, CH₂OR⁴, or a carboxylate salt of formula CO₂ ⁻R⁺;

R⁺ is Li⁺, Na⁺, K⁺, or NH₄ ⁺;

R is H, CH₃, C₂H₅, n-C₃H₇, or i-C₃H₇X is CH₂;

X is CH₂; R⁴ is H, COCH₃, or CH₃; and

R⁷, R⁸, R⁹ are independently H, CH₃, CH₃O;or R⁷ and R⁸ or R⁸ and R⁹ together constitute a carbonyl group (C═O),thus forming a cyclic carbonate;or OR⁸R¹ together form a cyclic ester (a lactone).

Among the especially preferred are compounds 1-6. Compound 1 iscommercially available from Biomol Research Laboratories, PlymouthMeeting, Pa., and compound 2 can be prepared as detailed in Lee et. al.,Biochemical and Biophysical Research Communications 1991, 180(3),1416-21. Compounds 3-6 can be prepared as described in examples 1-4below.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples which follow representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

Example 1 Synthesis of Compound 3

A solution of methyl ester 1 (20 mg, 0.104 mmol) in MeOH (2.1 mL)containing 1 M LiOH (0.5 mL, 0.5 mmol) was heated in a microwave heaterat 120° C. for 6 minutes. The reaction was concentrated and the residuewas chromatographed on a 10 mm diameter ×18 cm tall C18 reverse-phasesilica gel column eluting with 7:3 v:v 0.05 M HCl:acetonitrile to afforda crude white solid after concentration (40.9 mg). The solid was rinsedwith hot CH₃CN (2×2 mL) and the filtrate was concentrated to affordlactone 3 (7.8 mg, 47%). ¹³C NMR (150 MHz, dmso-d₆) δ 171.12 (C), 79.86(CH), 72.44 (CH), 62.03 (CH₂), 29.39 (CH₂), 21.67 (CH₂), 17.55 (CH₂).

Example 2 Synthesis of Compound 4

A solution of methyl ester 1 in aqueous MeOH is heated to reflux in thepresence of 3 equivalents of lithium hydroxide. After 6 h the reactionis cooled to room temperature and the pH of the solution is adjusted to6 by the addition of 70-9 mesh sulfonic acid resin MP (commerciallyavailable from Novabiochem/EMD Biosciences, 10394 Pacific Center Court,San Diego, Calif. 92121). The solution is filtered through a 0.2 μMpoly-terfluoroethylene syringe filter and concentrated to afford thelithium carboxylate 4 as a white solid. ¹H NMR (D₂O, 400 MHz) δ3.69-3.64 (m, 1H), 3.55-3.47 (m, 3H), 2.16-2.12 (m, 2H), 1.67-1.64 (m,1H), 1.54-1.48 (m, 2H), 1.38-1.34 (m, 1H). ¹³C NMR (D₂O, 100 MHz) δ183.46 (C), 74.61 (CH), 71.67 (CH), 62.49 (CH₂), 37.26 (CH₂), 31.55(CH₂), 22.04 (CH₂).

Example 3 Synthesis of Compound 8

2-deoxy-D-ribose is converted to the acetonide-protected lactol 10 bytreatment with 2-methoxypropene and catalytic pyridiniump-toluenesulfonate (PPTS) in ethyl acetate. Wittig reaction withPh₃P═CHCO₂Et in THF in the presence of catalytic benzoic acid affordsenoate 11, which is reduced to 12 under a hydrogen atmosphere in thepresence of catalytic Pd/C in ethanol. Deprotection of 12 using 0.1 NHCl in ethanol for 5 minutes, followed by quenching with aqueous NaHCO₃,affords 8 after silica gel chromatographic purification.

Example 4 Synthesis of Compound 9

Wittig reaction of lactol 10 with Ph₃P═CHCO₂Et in THF in the presence ofcatalytic benzoic acid affords enoate 13, which is reduced to 14 under ahydrogen atmosphere in the presence of catalytic Pd/C in isopropanol.Deprotection of 14 using 0.1 N HCl in isopropanol for 5 minutes,followed by quenching with aqueous NaHCO₃, affords 9 after silica gelchromatographic purification.

The present invention is also directed to compositions containing5,6,7-trihydroxyheptanoic acid and analogs and methods for their use.According to the methods of the present invention, a compositioncomprising one or more compounds of the present invention and apharmaceutically acceptable carrier for systemic or local administrationis administered to a mammal in need thereof. The compositions areformulated in accordance with methods known in the art for theparticular route of administration desired.

The compounds of the present invention can be administered eithersystemically or locally. Systemic administration includes: oral,transdermal, subdermal, intraperitioneal, subcutaneous, transnasal,sublingual, or rectal. Local administration for ocular administrationincludes: topical, intravitreal, periocular, transcleral, retrobulbar,sub-tenon, or via an intraocular device. Preferred administrationdepends on the type of ocular neovascular condition or disease beingtreated.

The compositions administered according to the present inventioncomprise a pharmaceutically effective amount of one or more compounds.As used herein, a “pharmaceutically effective amount” is one which issufficient to reduce or prevent neovascularization and/or edema.Generally, for compositions intended to be administered systemically forthe treatment of ocular neovascularization or edema, cancer, arthritis,or vascular restenosis secondary to cardiac angioplasty, the totalamount of compound will be about 0.01-100 mg/kg.

Included within the scope of the present invention are the individualenantiomers of the title compounds, as well as their racemic andnon-racemic mixtures. Generally, the individual enantiomers can beprocured by a number of methods, including but not limited to:enantioselective synthesis from the appropriate enantiomerically pure orenriched starting material; synthesis from racemic/non-racemic orachiral starting materials using a chiral reagent, catalyst, solvent,etc. (see for example: Asymmetric Synthesis, J. D. Morrison and J. W.Scott, Eds. Academic Press Publishers, (New York) 1985), volumes 1-5;Principles of Asymmetric Synthesis, R. E. Gawley and J. Aube, Eds.;Elsevier Publishers (Amsterdam 1996)); and isolation from racemic andnon-racemic mixtures by a number of known methods, e.g. by purificationof a sample by chiral HPLC (A Practical Guide to Chiral Separations byHPLC, G. Subramanian, Ed., VCH Publishers, (New York 1994); ChiralSeparations by HPLC, A. M. Krstulovic, Ed., Ellis Horwood Ltd.Publishers (1989)), or by enantioselective hydrolysis of a carboxylicacid ester sample by an enzyme (Ohno, M.; Otsuka, M., Organic Reactions,37:1 (1989)). Those skilled in the art will appreciate that racemic andnon-racemic mixtures may be obtained by several means, including withoutlimitation, nonenantioselective synthesis, partial resolution, or evenmixing samples having different enantiomeric ratios. Departures may bemade from such details within the scope of the accompanying claimswithout departing from the principles of the invention and withoutsacrificing its advantages. Also included within the scope of thepresent invention are the individual isomers substantially free of theirrespective enantiomers.

The following topical ophthalmic and systemic formulations are usefulaccording to the present invention administered 1-4 times per dayaccording to the discretion of a skilled clinician.

Example 5

Ingredients Amount (wt %) Compound of formula I, especially 0.01-2%Compound 1 Hydroxypropyl methylcellulose  0.5% Dibasic sodium phosphate(anhydrous)  0.2% Sodium chloride  0.5% Disodium EDTA (Edetate disodium)0.01% Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodiumhydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4 Purified waterq.s. to 100%

Example 6

Ingredients Amount (wt %) Compound of formula I, especially 0.01-2%Compound 4 Methyl cellulose  4.0% Dibasic sodium phosphate (anhydrous) 0.2% Sodium chloride  0.5% Disodium EDTA (Edetate disodium) 0.01%Polysorbate 80 0.05% Benzalkonium chloride 0.01% Sodiumhydroxide/Hydrochloric acid For adjusting pH to 7.3-7.4 Purified waterq.s. to 100%

Example 7

Ingredients Amount (wt %) Compound of formula I, especially 0.01-2%  Compound 2 Guar Gum 0.4-6.0% Dibasic sodium phosphate (anhydrous)  0.2%Sodium chloride  0.5% Disodium EDTA (Edetate disodium) 0.01% Polysorbate80 0.05% Benzalkonium chloride 0.01% Sodium hydroxide/Hydrochloric acidFor adjusting pH to 7.3-7.4 Purified water q.s. to 100%

Example 8

Ingredients Amount (wt %) Compound of formula I, especially 0.01-2%Compound 3 White petrolatum and mineral oil and Ointment consistencylanolin Dibasic sodium phosphate (anhydrous)  0.2% Sodium chloride  0.5%Disodium EDTA (Edetate disodium) 0.01% Polysorbate 80 0.05% Benzalkoniumchloride 0.01% Sodium hydroxide/Hydrochloric acid For adjusting pH to7.3-7.4

Example 9

10 mM IV Solution w/v % Compound of formula I, especially 0.384%Compound 4 L-Tartaric acid  2.31% Sodium hydroxide pH 3.8 Hydrochloricacid pH 3.8 Purified water q.s. to 100%

Example 10

5 mg Capsules mg/capsule Ingredient (Total Wt. 100 mg) Compound offormula I, especially 5 Compound 4 Lactose, anhydrous 55.7 Starch,Sodium carboxy-methyl 8 Cellulose, microcrystalline 30 Colloidal silicondioxide .5 Magnesium stearate .8

The preferred compositions of the present invention are intended foradministration to a human patient suffering from: dry AMD; an ocular NVor edematous disease or disorder, such as, diabetic retinopathy, chronicglaucoma, retinal detachment, sickle cell retinopathy, age-relatedmacular degeneration, rubeosis iritis, uveitis, neoplasms, Fuch'sheterochromic iridocyclitis, neovascular glaucoma, cornealneovascularization, neovascularization resulting from combinedvitrectomy and lensectomy, retinal ischemia, choroidal vascularinsufficiency, choroidal thrombosis, carotid artery ischemia, contusiveocular injury, retinopathy of prematurity, retinal vein occlusion,proliferative vitreoretinopathy, corneal angiogenesis, retinalmicrovasculopathy, and retinal (macular) edema; cancer; arthritis; andvascular restenosis secondary to a percutaneous transluminal coronaryangioplasty procedure.

This invention has been described by reference to certain preferredembodiments; however, it should be understood that it may be embodied inother specific forms or variations thereof without departing from itsspecial or essential characteristics. The embodiments described aboveare therefore considered to be illustrative in all respects and notrestrictive, the scope of the invention being indicated by the appendedclaims rather than by the foregoing description.

1. A method for treating persons suffering from a posterior segmentocular disease or a cellular hyperproliferative disorder, whichcomprises administering a pharmaceutically effective amount of one ormore compounds of formula I:

wherein: R¹ is C₂H₅, CO₂R, CONR²R³, CH₂OR⁴, or CH₂NR⁵R⁶; R is H, C₁-C₆straight chain or branched alkyl, C₃-C₆ straight chain or branchedalkenyl, C₃-C₆ straight chain or branched alkynyl, C₃-C₆ cycloalkyl, orphenyl; or R¹ is a carboxylate salt of formula CO₂ ⁻R⁺, where R⁺ is Li⁺,Na⁺, K⁺, or an R¹ ammonium moiety of formula ⁺NR¹⁰R¹²R¹³, where R¹⁰,R¹¹, R¹², and R¹³ are independently H or C₁-C₆ straight chain orbranched alkyl, each alkyl group optionally bearing an OH or OCH₃substituent; R², R³ are independently H, C₁-C₆ straight chain orbranched alkyl, C₃-C₆ straight chain or branched alkenyl, C₃-C₆ straightchain or branched alkynyl, C₃-C₆ cycloalkyl, benzyl, phenyl, OH, OCH₃,or OC₂H₅, provided that at most only one of R², R³ is OH, OCH₃, orOC₂H₅; R⁴ is H, C(O)R¹⁴, C₁-C₆ straight chain or branched alkyl, C₃-C₆straight chain or branched alkenyl, C₃-C₆ straight chain or branchedalkynyl, C₃-C₆ cycloalkyl benzyl, or phenyl; R⁵, R⁶ are independently H,C(O)R¹⁴ C₁-C₆ straight chain or branched alkyl, C₃-C₆ straight chain orbranched alkenyl, C₃-C₆ straight chain or branched alkynyl, C₃-C₆cycloalkyl, benzyl, phenyl, OH, OCH₃, or OC₂H₅, provided that at mostonly one of R⁵, R⁶ is OH, OCH₃, or OC₂H₅; X is O, CH₂, or S; R⁷, R⁸, andR⁹ are independently H, CH₃, C₂H₅, C(O)R¹⁴, C(O)NR¹⁴R¹⁵, or CO₂R¹⁵; orR⁷ and R⁸ or R⁸ and R⁹ together constitute a carbonyl group (C═O), thusforming a cyclic carbonate; or OR⁸R¹ together form a cyclic ester (alactone); R¹⁴ and R¹⁵ are H, C₁-C₆ straight chain or branched alkyl,C₃-C₆ straight chain or branched alkenyl, C₃-C₆ straight chain orbranched alkynyl, C₃-C₆ cycloalkyl, benzyl, or phenyl; and

indicates that the OR⁹ substituent can be arranged to afford the R or Sabsolute configuration at that position:


2. The method of claim 1, wherein the posterior segment ocular diseaseis dry AMD or a posterior segment ocular neovascular or edematousdisease.
 3. The method of claim 2, wherein for the compound(s) offormula I: R¹ is C₂H₅, CO₂R, CH₂OR⁴, or a carboxylate salt of formulaCO₂ ⁻R⁺; R⁺ is Li⁺, Na⁺, K⁺, or NH₄ ⁺; R is H, CH₃, C₂H₅, n-C₃H₇, ori-C₃H₇; X is CH₂; R⁴ is H, COCH₃, or CH₃; and R⁷, R⁸, R⁹ areindependently H, CH₃, CH₃CO; or R⁷ and R⁸ or R⁸ and R⁹ togetherconstitute a carbonyl group (C═O), thus forming a cyclic carbonate; orOR⁸R¹ together form a cyclic ester (a lactone).
 4. The method of claim3, wherein the compound(s) is(are) selected from the group consistingof:


5. The method of claim 2, wherein the posterior segment ocularneovascular or edematous disease is selected from the group consistingof diabetic retinopathy, wet AMD, retinal microvasculopathy, and retinal(macular) edema.
 6. The method of claim 3, wherein the posterior segmentocular neovascular or edematous disease is selected from the groupconsisting of diabetic retinopathy, wet AMD, retinal microvasculopathy,and retinal (macular) edema.
 7. The method of claim 4, wherein theposterior segment ocular neovascular or edematous disease is selectedfrom the group consisting of diabetic retinopathy, wet AMD, retinalmicrovasculopathy, and retinal (macular) edema
 8. A compositioncomprising a pharmaceutically effective amount of a compound of claim 2.9. The composition of claim 7, wherein said composition is an ophthalmiccomposition.
 10. The composition of claim 7, comprising from abut 0.01to about 100 mg/kg of the compound of claim
 1. 11. The composition ofclaim 7, comprising a compound of formula I:

wherein for the compound(s) of formula I: R¹ is C₂H₅, CO₂R, CH₂OR⁴, or acarboxylate salt of formula CO₂ ⁻R⁺; R⁺ is Li⁺, Na⁺, K⁺, or NH₄ ⁺; R isH, CH₃, C₂H₅, n-C₃H₇, or i-C₃H₇; X is CH₂; R⁴ is H, COCH₃, or CH₃; andR⁷, R⁸, R⁹ are independently H, CH₃, CH₃CO; or R⁷ and R⁸ or R⁸ and R⁹together constitute a carbonyl group (C═O), thus forming a cycliccarbonate; or OR⁸R¹ together form a cyclic ester (a lactone).
 12. Thecomposition of claim 10, wherein the compound is selected from the groupconsisting of:


13. The composition of claim 9, wherein the weight percent of thecompound in the composition is from 0.01 to 2 percent.
 14. Thecomposition of claim 7, wherein the composition is solution.
 15. Thecomposition of claim 13, wherein the concentration of the compound inthe solution is from about 0.2% to about 0.5% w/v %.
 16. The compositionof claim 14, wherein the compound is selected from the group consistingof:

where R is CH₃ or CO₂R forms a lithium carboxylate salt of formula CO₂⁻Li⁺.
 17. The composition of claim 7, wherein the composition is acapsule.
 18. The composition of claim 16, wherein the capsule comprisesfrom about 1 mg to about 10 mg compound.
 19. The composition of claim17, wherein the capsule comprises about 5 mg compound.
 20. Thecomposition of claim 18, wherein the compound is

where R is CH₃ or CO₂R forms a lithium carboxylate salt of formula CO₂⁻Li⁺.
 21. The composition of claim 7, wherein the composition is anophthalmic ointment.
 22. The composition of claim 20, wherein theconcentration of the compound is from about 0.01 percent to about 2percent.
 23. The composition of claim 21, wherein the compound is


24. The method of claim 1, wherein the cellular hyperproliferativedisorder is cancer.
 25. The method of claim 1, wherein the cellularhyperproliferative disorder is arthritis.
 26. The method of claim 1,wherein the cellular hyperproliferative disorder is vascular restenosissecondary to a percutaneous transluminal coronary angioplasty procedure.